Comparison of two-dimensional imaging to three-dimensional modeling of intrahepatic portosystemic shunts using computed tomography angiography.

Computed tomography angiography (CTA) is used for the diagnosis of intrahepatic portosystemic shunts (IHPSS). When planning for transcatheter intervention, caudal vena cava (CVC) measurements are typically obtained from two-dimensional (2D) imaging to aid in stent selection. We hypothesized that clinically applicable three-dimensional (3D) IHPSS models can be generated, and CVC measurements will not differ between 2D images and 3D models. Computed tomography angiography datasets from client-owned dogs with IHPSS at the University of Georgia Veterinary Teaching Hospital from 2016 to 2022 were analyzed. Materialise Mimics 25.0 and 3-matic 17.0 were used for 3D modeling. Caudal vena cava diameters were measured in 2D dorsal and transverse planes 20 mm cranial and caudal from the shunt ostium and were compared with CVC diameters from 3D models. Length was measured in the 2D dorsal plane between midpoints of each diameter and compared to the 3D model length. Data are presented as mean (SD), and intraclass correlation coefficients were performed. Three-dimensional models were generated for 32 IHPSS (15 right-, 12 left-, and five central-divisional). Two-dimensional dorsal and transverse area-associated diameter measurements were 16.7 mm (5.6) and 15.5 mm (4.2) cranial; 14.9 mm (4.2) and 14.3 mm (3.7) caudal. Three-dimensional area-associated diameter measurements were 15.3 mm (4.4) cranial and 14.0 mm (3.6) caudal. The 2D length was 61.5 mm (7.1) compared with 3D 59.9 mm (7.2). Intraclass correlation coefficients comparing 2D and 3D diameters were all >0.80, indicating very good agreement, with good agreement (>0.60) for length. Clinically applicable 3D IHPSS models can be generated using engineering software. Measurements from 3D models are consistent with 2D planar imaging. Both 2D CTA and 3D virtual models can be utilized for preprocedural planning, depending on clinician preference.

Genetic variants and effect modifiers of QT interval prolongation in patients with sickle cell disease.

BACKGROUND: Sickle cell disease (SCD) is a common inherited blood disorder among African Americans (AA), with premature mortality which has been associated with prolongation of the heart rate-corrected QT interval (QTc), a known risk factor for sudden cardiac death. Although numerous genetic variants have been identified as contributors to QT interval prolongation in the general population, their impact on SCD patients remains unclear. This study used an unweighted polygenic risk score (PRS) to validate the previously identified associations between SNPs and QTc interval in SCD patients, and to explore possible interactions with other factors that prolong QTc interval in AA individuals with SCD. METHODS: In SCD patients, candidate genetic variants associated with the QTc interval were genotyped. To identify any risk SNPs that may be correlated with QTc interval prolongation, linear regression was employed, and an unweighted PRS was subsequently constructed. The effect of PRS on the QTc interval was evaluated using linear regression, while stratification analysis was used to assess the influence of serum alanine transaminase (ALT), a biomarker for liver disease, on the PRS effect. We also evaluated the PRS with the two subcomponents of QTc, the QRS and JTc intervals. RESULTS: Out of 26 candidate SNPs, five risk SNPs were identified for QTc duration under the recessive model. For every unit increase in PRS, the QTc interval prolonged by 4.0 ms (95% CI: [2.0, 6.1]; p-value: <0.001) in the additive model and 9.4 ms in the recessive model (95% CI: [4.6, 14.1]; p-value: <0.001). Serum ALT showed a modification effect on PRS-QTc prolongation under the recessive model. In the normal ALT group, each PRS unit increased QTc interval by 11.7 ms (95% CI: [6.3, 17.1]; p-value: 2.60E-5), whereas this effect was not observed in the elevated ALT group (0.9 ms; 95% CI: [-7.0, 8.8]; p-value: 0.823). CONCLUSION: Several candidate genetic variants are associated with QTc interval prolongation in SCD patients, and serum ALT acts as a modifying factor. The association of a CPS1 gene variant in both QTc and JTc duration adds to NOS1AP as evidence of involvement of the urea cycle and nitric oxide metabolism in cardiac repolarization in SCD. Larger replication studies are needed to confirm these findings and elucidate the underlying mechanisms.

Forced labour risk is pervasive in the US land-based food supply.

Social risk assessments and case studies of labour conditions in food production primarily focus on specific subpopulations, regions and commodities. To date, research has not systematically assessed labour conditions against international standards across diverse, complex food products. Here we combine data on production, trade, labour intensity and qualitative risk coding to quantitatively assess the risk of forced labour embedded in the US land-based food supply, building on our previous assessment of fruits and vegetables. We demonstrate that animal-based proteins, processed fruits and vegetables, and discretionary foods are major contributors to forced labour risk and that 62% of total forced labour risk stems from domestic production or processing. Our findings reveal the widespread risk of forced labour present in the US food supply and the necessity of collaborative action across all countries-high, middle and low income-to eliminate reliance on labour exploitation.

A Decision Framework for Selecting Critically Important Nutrients from Aquatic Foods.

PURPOSE OF REVIEW: Aquatic foods are increasingly being recognized as a diverse, bioavailable source of nutrients, highlighting the importance of fisheries and aquaculture for human nutrition. However, studies focusing on the nutrient supply of aquatic foods often differ in the nutrients they examine, potentially biasing their contribution to nutrition security and leading to ineffective policies or management decisions. RECENT FINDINGS: We create a decision framework to effectively select nutrients in aquatic food research based on three key domains: human physiological importance, nutritional needs of the target population (demand), and nutrient availability in aquatic foods compared to other accessible dietary sources (supply). We highlight 41 nutrients that are physiologically important, exemplify the importance of aquatic foods relative to other food groups in the food system in terms of concentration per 100 g and apparent consumption, and provide future research pathways that we consider of high importance for aquatic food nutrition. Overall, our study provides a framework to select focal nutrients in aquatic food research and ensures a methodical approach to quantifying the importance of aquatic foods for nutrition security and public health.

The soluble guanylyl cyclase pathway is inhibited to evade androgen deprivation-induced senescence and enable progression to castration resistance.

Castration-resistant prostate cancer (CRPC) is fatal and therapeutically under-served. We describe a novel CRPC-restraining role for the vasodilatory soluble guanylyl cyclase (sGC) pathway. We discovered that sGC subunits are dysregulated during CRPC progression and its catalytic product, cyclic GMP (cGMP), is lowered in CRPC patients. Abrogating sGC heterodimer formation in castration-sensitive prostate cancer (CSPC) cells inhibited androgen deprivation (AD)-induced senescence, and promoted castration-resistant tumor growth. We found sGC is oxidatively inactivated in CRPC. Paradoxically, AD restored sGC activity in CRPC cells through redox-protective responses evoked to protect against AD-induced oxidative stress. sGC stimulation via its FDA-approved agonist, riociguat, inhibited castration-resistant growth, and the anti-tumor response correlated with elevated cGMP, indicating on-target sGC activity. Consistent with known sGC function, riociguat improved tumor oxygenation, decreasing the PC stem cell marker, CD44, and enhancing radiation-induced tumor suppression. Our studies thus provide the first evidence for therapeutically targeting sGC via riociguat to treat CRPC. Statement of significance: Prostate cancer is the second highest cancer-related cause of death for American men. Once patients progress to castration-resistant prostate cancer, the incurable and fatal stage, there are few viable treatment options available. Here we identify and characterize a new and clinically actionable target, the soluble guanylyl cyclase complex, in castration-resistant prostate cancer. Notably we find that repurposing the FDA-approved and safely tolerated sGC agonist, riociguat, decreases castration-resistant tumor growth and re-sensitizes these tumors to radiation therapy. Thus our study provides both new biology regarding the origins of castration resistance as well as a new and viable treatment option.

Longitudinal Predictors of Pain in Pediatric Sickle Cell Disease.

OBJECTIVE: Despite the identified pathophysiology of vaso-occlusive pain in sickle cell disease (SCD), predictors of pain in youth with SCD remain elusive. In this study, we measured changes in pain frequency, intensity, and interference over 1 year and examined biopsychosocial risk factors (SCD disease severity, age, female, depression, and sleep quality) as possible longitudinal predictors. METHODS: Medical history was obtained from retrospective chart review for 79 children with SCD (ages 2-18 years; 48.1% female; 100% Black/African American; 83.5% SCD, SS genotype). As part of a clinical screening protocol, caregivers (n = 79) and youth 8-18 years (n = 43) completed psychosocial questionnaires approximately 1 year apart (M = 15.52 months, SD = 5.69). Zero-order correlations, paired t-tests, and hierarchical linear models examined longitudinal predictors of pain. The longitudinal bidirectional relationship between pain and sleep was also examined. RESULTS: The rate of severe SCD disease increased from 41.8% to 55.7% across the year, while most hematologic medical parameters remained stable. Increased depression and pain interference at survey 1 significantly predicted increased pain interference at survey 2. Poor sleep quality and increased pain frequency at survey 1 predicted increased pain frequency at survey 2. Finally, increased pain interference at survey 1 predicted poor sleep quality at survey 2. DISCUSSION: History of pain, depression, and sleep quality were longitudinal predictors of pain over 1 year in youth with SCD. Identifying longitudinal predictors of pain may lead to earlier identification of patients with a high-risk SCD pain phenotype and earlier medical, psychological, and behavioral interventions.

An Evaluation of Research Publications for General Surgery Residents And its Influence on the Future Pursuit of Fellowship or Academic Career.

INTRODUCTION: Traditionally, the Accreditation Council for Graduate Medical Education (ACGME) requires residency programs to implement research and other scholarly activities into their training curriculum. Encouraging residents to publish during residency is believed to promote research throughout their careers; however, the rate of research outcomes among general surgery residents remains unknown. Our study aims to determine associated factors that influence publication rates before, during, and after general surgery residency. METHODS: This observational study employed a cross-sectional design. We examined whether research outcomes during general surgery residency was associated with academic advancement or continued research involvement after residency. We identified 321 general surgery residency programs on the Doximity website and randomly selected 50 to include in our sample. Of these programs, graduate rosters for 31 programs were located and subsequently included. Of the 405 residency graduates identified, we recorded the number of peer-reviewed publications, H-indices, fellowships, and whether the graduate pursued a career in private practice or academia. RESULTS: Among the 405 physicians analyzed, 3815 total publications were identified with a mean of 9.4 (SD 11.8) per person. The most reported study design was observational studies (46.5%; 1775/3815) and the least reported was systematic reviews/meta-analyses (1.4%; 52/3815). The number of publications before residency positively correlated with having a higher h-index (r = 0.4). We also found that physicians who completed a fellowship had more publications during residency (mean = 4.7, SD = 6.5) than those not pursuing a fellowship (mean = 1.5, SD = 2.7; t= -4.3. p ≤ 0.001). We observed a statistically significant increase in the likelihood a physician pursued a career in academic medicine if they pursued a fellowship (OR: 3.77, 95% CI: 2.0-7.2) and if they had published research as a primary author (OR 1.25, 95% CI: 1.0-1.5). CONCLUSION: Increased research productivity was associated with continued academic pursuits and an increased likelihood of pursuing fellowship training after residency.

Clinical and Laboratory Correlates of QTc Duration in Adult and Pediatric Sickle Cell Disease.

Background: Sickle cell disease, a common genetic disorder in African Americans, manifests an increased risk of sudden death, the basis of which is incompletely understood. Prolongation of heart rate-corrected QT (QTc) interval on the electrocardiogram, a standard clinical measure of cardiac repolarization, may contribute to sudden death by predisposing to torsades de pointes ventricular tachycardia. Methods: We established a cohort study of 293 adult and 121 pediatric sickle cell disease patients drawn from the same geographic region as the Jackson Heart Study (JHS) cohort, in which significant correlates of QT duration have been characterized and quantitatively modeled. Herein, we establish clinical and laboratory correlates of QTc duration in our cohort using stepwise multivariate linear regression analysis. We then compared our adult sickle cell disease data to effect-size predictions from the published JHS statistical model of QT interval duration. Results: In adult sickle cell disease, gender, diuretic use, QRS duration, serum ALT levels, anion gap, and diastolic blood pressure show positive correlation; hemoglobin levels show inverse correlation; in pediatric sickle cell disease, age, hemoglobin levels, and serum bicarbonate and creatinine levels show inverse correlation. The mean QTc in our adult sickle cell disease cohort is 7.8 milliseconds longer than in the JHS cohort, even though the JHS statistical model predicts that the mean QTc in our cohort should be > 11 milliseconds shorter than in the much older JHS cohort, a differential of > 18 milliseconds. Conclusion: Sickle cell disease patients have substantial QTc prolongation relative to their age, driven by factors some overlapping, in adult and pediatric sickle cell disease, and distinct from those that have been defined in the general African American community.

Prevalence of raised body mass index in paediatric sickle cell disease.

AIM: Children with sickle cell disease (SCD) have historically weighed less than their healthy peers. More recently, a retrospective chart review from six institutions in New England reported nearly one-quarter of children and adolescents with SCD had raised body mass index (BMI). This study aimed to examine rates of children with SCD with raised BMI in Mississippi compared to state and national norms and assess the correlation between haemoglobin and BMI. METHODS: A retrospective chart review of paediatric patients with SCD at the University of Mississippi Medical Center (UMMC) was conducted using data from the most recent clinic visit. Mississippi and national weight status estimates for youth 10-17 years were obtained from the 2016-2017 National Survey of Children's Health. RESULTS: For youth 10-17 years with SCD (n = 345), 21.4.% of children with SS/Sß° and 36.1% with SC/Sß+ had raised BMI compared to Mississippi and national rates, 39.2 and 31%, respectively. The prevalence of children with raised BMI with SC/Sß+ did not differ from state and national rates, while children with SS/Sß° were half as likely as their Mississippi peers to have raised BMI. Haemoglobin levels were different among children with SCD who had low BMI (8.80 g/dL), average BMI (9.2 g/dL) and raised BMI (10.5 g/dL) (P < 0.001). CONCLUSIONS: Children with SCD evaluated at UMMC have similar rates of raised BMI compared to state and national norms. Children with raised BMI have higher mean haemoglobin levels compared to children with SCD with low or average BMI. IMPLICATIONS AND CONTRIBUTION: Historically, patients with SCD have been underweight and normal weight. Our paediatric and adolescent patients with SCD now have prevalence rates of raised BMI that approach state and national rates. Further work must be done to determine whether this reflects healthier children with SCD or raises concerns about life-style-related comorbidities.

Diet Sustainability Analyses Can Be Improved With Updates to the Food Commodity Intake Database.

Diet sustainability analyses inform policymaking decisions and provide clinicians and consumers with evidence-based information to make dietary changes. In the United States, the Food Commodity Intake Database (FCID) provides a crosswalk for integrating nationally representative data on food intake from the National Health and Nutrition Examination Survey (NHANES) with data on sustainability outcomes from other publicly available databases. However, FCID has not been updated since 2010 and does not link with contemporary NHANES data, which limits further advancements in sustainability research. This study fills this research gap by establishing novel linkages between FCID and NHANES 2011-2018, comparing daily per capita food intake with and without these linkages, and making these data publicly available for use by other researchers. To update FCID, two investigators independently established novel data linkages, a third investigator resolved discrepancies, and a fourth investigator audited linkages for accuracy. Dietary data were acquired from nearly 45,000 adults from 2001 to 2018, and food intake was compared between updated vs. non-updated FCID versions. Total food intake from 2011 to 2018 was 5-23% higher using the updated FCID compared to the non-updated version, and intake was over 100% higher in some years for some food categories including poultry, eggs, legumes, starchy vegetables, and tropical oils (P < 0.001 for all comparisons). Further efforts may be needed to create new food composition data to reflect new products and reformulations that enter the food supply over time. This study removes a barrier to further diet sustainability analyses by establishing a data crosswalk between contemporary NHANES and other publicly available databases on agricultural resource use, environmental impacts, and consumer food expenditures.

Assessment of a Plasma Amyloid Probability Score to Estimate Amyloid Positron Emission Tomography Findings Among Adults With Cognitive Impairment.

Importance: The diagnostic evaluation for Alzheimer disease may be improved by a blood-based diagnostic test identifying presence of brain amyloid plaque pathology. Objective: To determine the clinical performance associated with a diagnostic algorithm incorporating plasma amyloid-ß (Aß) 42:40 ratio, patient age, and apoE proteotype to identify brain amyloid status. Design, Setting, and Participants: This cohort study includes analysis from 2 independent cross-sectional cohort studies: the discovery cohort of the Plasma Test for Amyloidosis Risk Screening (PARIS) study, a prospective add-on to the Imaging Dementia-Evidence for Amyloid Scanning study, including 249 patients from 2018 to 2019, and MissionAD, a dataset of 437 biobanked patient samples obtained at screenings during 2016 to 2019. Data were analyzed from May to November 2020. Exposures: Amyloid detected in blood and by positron emission tomography (PET) imaging. Main Outcomes and Measures: The main outcome was the diagnostic performance of plasma Aß42:40 ratio, together with apoE proteotype and age, for identifying amyloid PET status, assessed by accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC). Results: All 686 participants (mean [SD] age 73.2 [6.3] years; 368 [53.6%] men; 378 participants [55.1%] with amyloid PET findings) had symptoms of mild cognitive impairment or mild dementia. The AUC of plasma Aß42:40 ratio for PARIS was 0.79 (95% CI, 0.73-0.85) and 0.86 (95% CI, 0.82-0.89) for MissionAD. Ratio cutoffs for Aß42:40 based on the Youden index were similar between cohorts (PARIS: 0.089; MissionAD: 0.092). A logistic regression model (LRM) incorporating Aß42:40 ratio, apoE proteotype, and age improved diagnostic performance within each cohort (PARIS: AUC, 0.86 [95% CI, 0.81-0.91]; MissionAD: AUC, 0.89 [95% CI, 0.86-0.92]), and overall accuracy was 78% (95% CI, 72%-83%) for PARIS and 83% (95% CI, 79%-86%) for MissionAD. The model developed on the prospectively collected samples from PARIS performed well on the MissionAD samples (AUC, 0.88 [95% CI, 0.84-0.91]; accuracy, 78% [95% CI, 74%-82%]). Training the LRM on combined cohorts yielded an AUC of 0.88 (95% CI, 0.85-0.91) and accuracy of 81% (95% CI, 78%-84%). The output of this LRM is the Amyloid Probability Score (APS). For clinical use, 2 APS cutoff values were established yielding 3 categories, with low, intermediate, and high likelihood of brain amyloid plaque pathology. Conclusions and Relevance: These findings suggest that this blood biomarker test could allow for distinguishing individuals with brain amyloid-positive PET findings from individuals with amyloid-negative PET findings and serve as an aid for Alzheimer disease diagnosis.

Trends in inpatient palliative care use for primary brain malignancies.

INTRODUCTION: Primary brain malignancies (PBMs) pose significant morbidity and poor prognosis. Despite NCCN recommendations that palliative care should be integrated into general oncologic care plans, it has been historically underused in patients with PBM. We sought to examine trends and factors associated with inpatient palliative care use in patients with PBM. METHODS: Data from the 2007-2016 National (Nationwide) Inpatient Sample was analyzed for descriptive statistics and trends. Multivariable logistic regression was used to identify factors associated with inpatient palliative care in patients with PBMs. RESULTS: Of the 510,238 observed hospitalizations of adults with PBM in a 10-year period, 37,365 (7.3%) had an associated inpatient palliative care consult. Rates of inpatient palliative care have increased significantly over the 10-year period, from 2.3 in 2007 to 11.9% in 2011. Patients receiving inpatient palliative care were less likely to receive inpatient oncologic treatment such as brain surgery, chemotherapy, or radiation compared to those without palliative care (14.6% with palliative care vs. 42.4% without, p < 0.001). They were more likely to receive life-sustaining treatments such as intubation, mechanical ventilation, tracheostomy, nutritional support, hemodialysis, or CPR (21.0% with palliative care vs. 10.4% without, p < 0.001). Palliative care was associated with decreased cost of admission ($18,602 with palliative care vs. $20,077 without). In a multiple variable logistic regression, age, non-elective admission, comorbidities, history of chemotherapy and radiation, and mechanical ventilation were associated with significantly increased odds of receiving palliative care. CONCLUSIONS: Inpatient palliative care utilization for patients hospitalized with PBM significantly increased between 2007 and 2016, though the service is still underutilized in the context of the severe symptoms and poor prognosis associated with PBM.

The PrecivityAD™ test: Accurate and reliable LC-MS/MS assays for quantifying plasma amyloid beta 40 and 42 and apolipoprotein E proteotype for the assessment of brain amyloidosis.

BACKGROUND: There is an unmet need for an accessible, less invasive, cost-effective method to facilitate clinical trial enrollment and aid in clinical Alzheimer's disease (AD) diagnosis. APOE genotype affects the clearance and deposition of amyloid-beta (Aß) with APOE4 carriers having increased risk while APOE2 alleles appear to be protective. Lower plasma Aß42/40 correlates with brain amyloidosis. In response, C2N has developed the PrecivityAD™ test; plasma LC-MS/MS assays for Aß isoform quantitation and qualitative APOE isoform-specific proteotyping. METHODS: In accord with CLIA standards, we developed and validated assay performance: precision, accuracy, linearity, limit of detection (LoD), interferences. RESULTS: Within-day precision varied from 1.5-3.0% (Aß40) and 2.5-8.4% (Aß42). Total (within-lab) variability was 2.7-7.7% (Aß40) and 3.1-9.5% (Aß42). Aß40 quantitation was linear from 10 to 1780 pg/mL; Aß42 was linear from 2 to 254 pg/mL. LoD was 11 and 2 pg/mL for Aß40 and Aß42, respectively. APOE proteotypes were 100% concordant with genotype, while LoD (fM) was much lower than APOE concentrations observed in plasma (mM). CONCLUSIONS: The PrecivityAD™ assays are precise, accurate, sensitive, and linear over a wide analytical range, free from significant interferences, and suitable for use in the clinical laboratory.

A blood-based diagnostic test incorporating plasma Aß42/40 ratio, ApoE proteotype, and age accurately identifies brain amyloid status: findings from a multi cohort validity analysis.

BACKGROUND: The development of blood-based biomarker tests that are accurate and robust for Alzheimer's disease (AD) pathology have the potential to aid clinical diagnosis and facilitate enrollment in AD drug trials. We developed a high-resolution mass spectrometry (MS)-based test that quantifies plasma Aß42 and Aß40 concentrations and identifies the ApoE proteotype. We evaluated robustness, clinical performance, and commercial viability of this MS biomarker assay for distinguishing brain amyloid status. METHODS: We used the novel MS assay to analyze 414 plasma samples that were collected, processed, and stored using site-specific protocols, from six independent US cohorts. We used receiver operating characteristic curve (ROC) analyses to assess assay performance and accuracy for predicting amyloid status (positive, negative, and standard uptake value ratio; SUVR). After plasma analysis, sites shared brain amyloid status, defined using diverse, site-specific methods and cutoff values; amyloid PET imaging using various tracers or CSF Aß42/40 ratio. RESULTS: Plasma Aß42/40 ratio was significantly (p < 0.001) lower in the amyloid positive vs. negative participants in each cohort. The area under the ROC curve (AUC-ROC) was 0.81 (95% CI = 0.77-0.85) and the percent agreement between plasma Aß42/40 and amyloid positivity was 75% at the optimal (Youden index) cutoff value. The AUC-ROC (0.86; 95% CI = 0.82-0.90) and accuracy (81%) for the plasma Aß42/40 ratio improved after controlling for cohort heterogeneity. The AUC-ROC (0.90; 95% CI = 0.87-0.93) and accuracy (86%) improved further when Aß42/40, ApoE4 copy number and participant age were included in the model. CONCLUSIONS: This mass spectrometry-based plasma biomarker test: has strong diagnostic performance; can accurately distinguish brain amyloid positive from amyloid negative individuals; may aid in the diagnostic evaluation process for Alzheimer's disease; and may enhance the efficiency of enrolling participants into Alzheimer's disease drug trials.

How to Be a Friend Who Is a Physician Without Being a Physician Friend.

As physicians, we are often asked for advice when loved ones become ill. Sometimes, the request advice is explicit; often, it is more supportive in nature and this may blur the boundary between being a friend and being a physician. Through various excerpts from social medial exchange, this narrative discusses the experience with a friend who was diagnosed with head and neck cancer during my Palliative Medicine Fellowship.

Fibronectin has multifunctional roles in posterior capsular opacification (PCO).

Fibrotic posterior capsular opacification (PCO), one of the major complications of cataract surgery, occurs when lens epithelial cells (LCs) left behind post cataract surgery (PCS) undergo epithelial to mesenchymal transition, migrate into the optical axis and produce opaque scar tissue. LCs left behind PCS robustly produce fibronectin, although its roles in fibrotic PCO are not known. In order to determine the function of fibronectin in PCO pathogenesis, we created mice lacking the fibronectin gene (FN conditional knock out -FNcKO) from the lens. While animals from this line have normal lenses, upon lens fiber cell removal which models cataract surgery, FNcKO LCs exhibit a greatly attenuated fibrotic response from 3 days PCS onward as assessed by a reduction in surgery-induced cell proliferation, and fibrotic extracellular matrix (ECM) production and deposition. This is correlated with less upregulation of Transforming Growth Factor ß (TGFß) and integrin signaling in FNcKO LCs PCS concomitant with sustained Bone Morphogenetic Protein (BMP) signaling and elevation of the epithelial cell marker E cadherin. Although the initial fibrotic response of FNcKO LCs was qualitatively normal at 48 h PCS as measured by the upregulation of fibrotic marker protein αSMA, RNA sequencing revealed that the fibrotic response was already quantitatively attenuated at this time, as measured by the upregulation of mRNAs encoding molecules that control, and are controlled by, TGFß signaling, including many known markers of fibrosis. Most notably, gremlin-1, a known regulator of TGFß superfamily signaling, was upregulated sharply in WT LCs PCS, while this response was attenuated in FNcKO LCs. As exogenous administration of either active TGFß1 or gremlin-1 to FNcKO lens capsular bags rescued the attenuated fibrotic response of fibronectin null LCs PCS including the loss of SMAD2/3 phosphorylation, this suggests that fibronectin plays multifunctional roles in fibrotic PCO development.

Physical Activity and Pain in Youth With Sickle Cell Disease.

Study objectives were to examine the relationships between physical activity, pain, and psychological distress in youth 8 to 17 years of age with sickle cell disease. Participants were 206 youth with sickle cell disease (M = 11.73 years, 54.9% female, 99.5% African American). Caregivers and youth completed a clinical psychosocial screening battery. Results revealed frequent pain (37.6%), moderate median pain intensity, and elevated median pain interference in youth. Lower caregiver-reported physical activity was associated with worse pain outcomes. Increased anxiety was also associated with worse pain outcomes. A better understanding of the relationship between physical activity/inactivity and pain will guide multifactorial treatment interventions.

Effects of Aryl Hydrocarbon Receptor Deficiency on PCB-77-Induced Impairment of Glucose Homeostasis during Weight Loss in Male and Female Obese Mice.

BACKGROUND: Lipophilic polychlorinated biphenyls (PCBs) accumulate with obesity, but during weight loss, liberated PCBs act as ligands of the aryl hydrocarbon receptor (AhR) to negatively influence health. Previous studies demonstrated that PCB-77 administration to obese male mice impaired glucose tolerance during weight loss. Recent studies indicate higher toxic equivalencies of dioxin-like PCBs in exposed females than males. OBJECTIVES: We compared effects of PCB-77 on weight gain or loss and glucose homeostasis in male vs. female mice. We defined effects of AhR deficiency during weight gain or loss in male and female mice exposed to PCB-77. METHODS: Study design was vehicle (VEH) or PCB-77 administration while fed a high-fat (HF) diet for 12 wk, followed by weight loss for 4 wk. The following groups were examined: male and female C57BL/6 mice administered VEH or PCB-77, female [Formula: see text] and [Formula: see text] mice administered VEH or PCB-77, and male [Formula: see text] and [Formula: see text] mice administered PCB-77. Glucose tolerance was quantified during weight gain (week 11) and loss (week 15); liver and adipose AhR and IRS2 (insulin receptor substrate 2) mRNA abundance, and PCB-77 concentrations were quantified at week 16. RESULTS: PCB-77 attenuated development of obesity in females but not males. During weight loss, PCB-77 impaired glucose tolerance of males. AhR-deficient females (VEH) were resistant to diet-induced obesity. Compared with VEH-treated mice, HF-fed [Formula: see text] females treated with PCB-77 has less weight gain, and [Formula: see text] females had greater weight gain. During weight loss, [Formula: see text] females but not [Formula: see text] males treated with PCB-77 exhibited impaired glucose tolerance. In [Formula: see text] females administered PCB-77, IRS2 mRNA abundance was lower in adipose tissue compared with VEH-treated mice. CONCLUSION: Male and female mice responded differently to PCB-77 and AhR deficiency in body weight (BW) regulation and glucose homeostasis. AhR deficiency reversed PCB-77-induced glucose impairment of obese males losing weight but augmented glucose intolerance of females. These results demonstrate sex differences in PCB-77-induced regulation of glucose homeostasis of mice. https://doi.org/10.1289/EHP4133.

Administration of low dose triclosan to pregnant ewes results in placental uptake and reduced estradiol sulfotransferase activity in fetal liver and placenta.

Sulfonation is a major pathway of estrogen biotransformation with a role in regulating estrogen homeostasis in humans and sheep. Previous in vitro studies found that triclosan is an especially potent competitive inhibitor of ovine placental estrogen sulfotransferase, with Kic of <0.1 nM. As the placenta is the main organ responsible for estrogen synthesis in pregnancy in both women and sheep, and the liver is another site of estrogen biotransformation, this study examined the effects of triclosan exposure of pregnant ewes on placental and hepatic sulfotransferase activity. Triclosan, 0.1 mg/kg/day, or saline vehicle was administered to late gestation fetal sheep for two days either by direct infusion into the fetal circulation or infusion into the maternal blood. On the third day, fetal liver and placenta were harvested and analyzed for triclosan and for cytosolic estradiol sulfotransferase activity. Placenta contained higher concentrations of triclosan than liver in each individual sheep in both treatment groups. There was a negative correlation between triclosan tissue concentration (pmol/g tissue) and cytosolic sulfotransferase activity (pmol/min/mg protein) towards estradiol. These findings demonstrated that in the sheep exposed to very low concentrations of triclosan, this substance is taken up into placenta and reduces estrogen sulfonation.

Adipose Tissue as a Site of Toxin Accumulation.

We examine the role of adipose tissue, typically considered an energy storage site, as a potential site of toxicant accumulation. Although the production of most persistent organic pollutants (POPs) was banned years ago, these toxicants persist in the environment due to their resistance to biodegradation and widespread distribution in various environmental forms (e.g., vapor, sediment, and water). As a result, human exposure to these toxicants is inevitable. Largely due to their lipophilicity, POPs bioaccumulate in adipose tissue, resulting in greater body burdens of these environmental toxicants with obesity. POPs of major concern include polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins and furans (PCDDs/PCDFs), and polybrominated biphenyls and diphenyl ethers (PBBs/PBDEs), among other organic compounds. In this review, we (i) highlight the physical characteristics of toxicants that enable them to partition into and remain stored in adipose tissue, (ii) discuss the specific mechanisms of action by which these toxicants act to influence adipocyte function, and (iii) review associations between POP exposures and the development of obesity and diabetes. An area of controversy relates to the relative potential beneficial versus hazardous health effects of toxicant sequestration in adipose tissue. © 2017 American Physiological Society. Compr Physiol 7:1085-1135, 2017.